Carcinogen-induced DNA depurination plays a central event in the initiation of cancer. Apurinic sites formed by carcinogens in this manner are mutated by errorprone repair. Studies indicate a remarkable similarity in the enzymatic (redox) mechanisms for the conversion of several carcinogens (diethylstilbestrol, hexestrol and benzene) and suspected agents for the initiation of neurodegenerative diseases (dopamine) into DNA-reactive metabolites. These chemicals primarily form DNA depurinating adducts. On the basis of these shared similarities, we hypothesize that these carcinogens (diethylstilbestrol and benzene) and dopamine cause disease through specific mutagenesis, induce mutations by error-prone repair. To examine this hypothesis, we have chosen three model systems (mouse skin H-ras, rat bone marrow N-ras and rat brain protein kinase C-gamma) to study the mechanism of mutagenesis by these agents. We have also noted that during the repair of carcinogen-induced DNA depurination, the level of AP endonuclease protein increases five-fold over untreated tissue levels. AP endonuclease is a multifunctional protein, with apurinic/apyrimidinic site incision activity (DNA repair) and a reducing activity on various transcription factors (redox activity). The redox status of AP endonuclease protein determines its ability to participate in DNA repair. We hypothesize that AP endonuclease induction plays important regulatory role in carcinogen-induced apurinic site repair. To examine these hypotheses, we propose four specific aims. In Specific Aim 1, we propose to examine the induction of mutations by the quinone of diethylstilbestrol in the mouse skin H-ras gene as a reporter system. In Specific Aim 2, we propose to examine induction of mutations by the quinone of benzene in the rat bone marrow N-ras model system for leukemia. In Specific Aim 3, we propose to examine induction of mutations by the quinone of dopamine in rat brain protein kinase C-gamma model system for neurodegenerative diseases. In Specific Aim 4, we propose to examine the induction of AP endonuclease by these chemicals in the model tissues, determine the apurinic/apyrimidininc site incision activity and the redox status of AP endonuclease protein. In summary, the proposed studies (Specific Aims 1-3) will provide experimental evidence on the central role of apurinic site induction plays in causing various diseases. Experiments proposed in Specific Aim 4 will examine the redox status of AP endonuclease and its role in apuinic site misrepair.